The present invention is novel derivatives of fenamic acids. Such fenamic acids include mefenamic acids of U.S. Pat. No. 3,138,636; flufenamic acids of U.S. Pat. No. 3,144,387 meclofenamate and tolfenamic acids of U.S. Pat. No. 3,313,848; and niflumic acids, flunixin, and olonixin of U.S. Pat. No. 26,655.
Other anthranilic acid derivatives of the fenamic series previously known include the generic compounds of the British Patent No. 989,951 or formula ##STR1## wherein Ar is .alpha.,.alpha.,.alpha.-trifuoro-m-tolyl; 2,3-xylyl, or 2,6-dichloro-m-tolyl, in U.S. Pat. No. 3,852,333.
The present novel derivatives include selected hydroxamic acids thereof which are heretofore unknown.
Among related aminobenzhydroxamic acids previously disclosed are compounds of the formula ##STR2## wherein R' is a saturated fatty hydrocarbon radical; phenyl, phenylalkyl, wherein the rings are optionally substituted by lower alkyl or lower alkoxy; or an aromatic heterocyclic group. This disclosure is in Japanese Application 24578/67, filed Apr. 2, 1964 by the Takeda Chemical Industry Co., Ltd. as an o-aminobenzhydroxamic acid analgesic derivative having less toxicity and analgesic, anticatarrhic, and antifebrile activity.
Other related disclosures include U.S. Pat. No. 4,029,815 to compounds of the formula ##STR3## wherein X.sub.5 is trifluoromethyl, difluoromethyl, or nitro, X.sub.4 is H, Br, Cl, or nitro, and Q may be NHOH. These compounds have utility as antidiarrheal agents.
Cyclized o-aminobenzhydroxamic-O-methylesters of the formula ##STR4## wherein R" is alkyl, aralkyl, or a basic side chain and R'" is H, Cl, or Br; are disclosed by Wolf, E. and Kohl, H. in "Cyclisiarungareaktionen von am Aminostickstoff Substituierten o-Aminobenz-hydroxamsaure-O-methylesteror," Ann. Chem. Liebigs, 1975, 1245-1251.
Wolf and Kohl also disclose an intermediate hydroxamic acid derivative from which the cyclized o-aminobenzhydroxamic-O-methylesters are made. The intermediate is ##STR5## wherein R.sub.c, R.sub.e, and R.sub.d are as defined below.
Other cyolized o-aminobenzyhydroxamic acids disclosed are ##STR6## wherein R.sub.a is CH.sub.2 CO.sub.2 C.sub.2 H.sub.5, C.sub.6 H.sub.3 Cl(p)NO2(m) and suggesting that R.sub.a may also be SO.sub.2 C.sub.6 H.sub.4 CH.sub.3 (p); and ##STR7## wherein R.sub.b is H or phenyl; R.sub.c is H, CH.sub.2 C.sub.6 H.sub.5, C.sub.6 H.sub.4 Cl(p), CH.sub.2 C.sub.6 H.sub.4 Cl(p), C.sub.6 H.sub.5, or CH.sub.3 ; R.sub.e is H or NO.sub.2 ; and R.sub.d is H or Cl. However, Wolf and Kohl do not disclose activity for these cyclized compounds and, further, do not make obvious the present invention.
Broadly, hydroxamic acid derivatives of selected aryl ring systems are disclosed in European Application Publication No. 0 196 184 having surprisingly high potency particularly by inhalation, oral efficacy, and with a surprisingly long duration of action. However, these aryl ring systems are in no way related to the present fenamic acid type compounds.
Two disclosures by Summers et al, (1) J. Med. Chem., 1987, 30, 574-80 and (2) In Vivo Characterization of Hydroxamic Acid Inhibitors of 5-Lipoxygenase disclosed at a seminar in early September, 1987 (Abstract) disclose hydroxamic acids as inhibitors of 5-lipoxygenase, however, the disclosures do not extend beyond very limited representative examples not including any fenamic acid derivatives.
Additional references related to the present invention, particularly for the substituents therein for L.sub.1 and L.sub.2, include a disclosure for reduction of the substituent in the carboxy-containing side chain of anilinophenyl group in J55013-227 of Derwent Abstract No. 17678C/10; and various fused nitrogen-containing ring systems in J54151-963 in Derwent Abstract No. 02846C/02, J54073-771 in Derwent Abstract No. 55094B/30, J54073-750 in Derwent Abstract No. 550855/30, J54073-737 in Derwent Abstract No. 55078B/30, J54070-265 in Derwent Abstract No. 51907B/28, J54063-073 in Derwent Abstract No. 48163B/26, J54063-042 in Derwent Abstract No. 48147B/26, DL-134-520 in Derwent Abstract No. 39059B/21, and JA2489/67 in Derwent Abstract No. 29861, U.S. Pat. No. 3,325,499 in Derwent Abstract No. 27,108 and 3,317,524 in Derwent Abstract No. 26,495.
Also in CA73(2):10333g 1-phenyl-3-isatinoxime is disclosed. The compounds disclosed in each of these references is not now the present invention because the particular substituents noted as L.sub.1 and NOR.sub.7 found in the present invention are not included or made obvious from the references.
Thus, the present invention are to selected novel derivatives of fenamates and pharmaceutically acceptable acid addition or base salts thereof, pharmaceutical compositions for treating inflammation, arthritis, pain, pyrrhia, and the methods for such treatment.
Finally, known related cyclized compounds include the quinazolinedione derivatives disclosed in U.S. Pat. No. 3,794,643 which are different from the present cyclized derivatives by unobvious substituents, particularly at the nitrogen between the carbonyls.